Gingivobuccal cancer (GBC) is the most common oral cavity cancer (OCC). Its incidence is increasing with increased use of tobacco and areca nut chewing in third world countries especially the Indian subcontinent. It comprises buccal mucosa, gingivobuccal sulcus, alveolus and retromolar area cancers. OCCs comprise 12% of all male cancers in India, 40% of these are GBCs. Certain precancerous conditions and lesions such as submucous fibrosis, leukoplakia and erythroplakia are known. In special situations such as trismus, examination and early detection becomes difficult. Computed tomography scan is an investigation of choice. Tumor node metastasis staging gives adequate information for treatment selection and prognosis. Surgery remains the mainstay of curative treatment. Due to its unique proximity to mandible and posteriorly infratemporal fossa, extent of surgery remains critical to provide cure with satisfactory functional and esthetic outcomes. Marginal mandibulectomy has consistently provided these results in carefully selected patients. More advanced cancers need segmental or hemimandibulectomy and appropriate reconstruction-preferably free microvascular bone and soft-tissue transfer. Radiotherapy is used in adjuvant setting to reduce locoregional recurrences. It can also be used as palliative modality in advance cases. The role of chemotherapy is investigational; however, criteria have been defined for its use concurrent with radiation in adjuvant postoperative settings in high-risk patients. Cure rates are as high as 85% in early stages and as low as 0%–20% in advance stages. Follow-up strategy is aimed at detection of locoregional failure initially and prevention and management of second cancers.

Squamous cell carcinoma (SCC) of head-and-neck has marked variation in incidence and mortality worldwide. This is because common SCC subsites are markedly variable depending on environmental, cultural, and genetic risk factors. Cancer of oral cavity accounts for 2%–6% of all cancers and 30% of all head-and-neck cancers.[1],[2]

India has one of the highest incidences of oral cancer in the world.[3] Oral cancer ranks number one among men and number three among women in India. Oral cancer constitutes 12% of all cancers in men and 8% of all cancers among women.[4] In India, the age-standardized incidence rate of oral cancer is 10.1 for men.[5]

The most common subsite involved in oral cavity cancer (OCC) in Indian communities in Africa and Southeast Asia is gingivobuccal cancer (GBC) (about 40% of all); while in Western world its rate is around 10%.[6] GBC has been aptly described as the “Indian Oral Cancer”.[1] GBC are unique and predominantly common OCC in the Indian subcontinent. Two- and five-year overall survival is about 63% and 53%, respectively, in apex institutes.[6]

Etiology

Tobacco and areca nut are the most common cause of GBC, and the immigrants from South Asian countries to Western world show typically more incidence.[7] These substances are being used with different names and preparations such as gutkha, mava, chinkani (snuff), khaini. They cause site specific SCC where they are placed, typically bucco alveolar (BA) sulcus or gingivolabial sulcus. Increasing alcohol and tobacco consumption significantly elevates the risk of the development of SCC.[8] Certain dietary deficiencies such as iron, Vitamin A, C, and E are associated with oral cancers.[2]

Chronic trauma by teeth or dentures and poor oral hygiene are also implied as cause of these cancers.[9] Lately, there is an up rise in literature regarding the causative effect of HPV (principally type 16). The detection of HPV DNA plus E6 and E7 region E6*I mRNA of only 3.9% is reported for oral cancers. This leads to the conclusion that HPV attributable fraction in oral cancer is very low in comparison to oropharyngeal cancers.[10] Submucous fibrosis (SMF) is proved to be a precancerous condition, a major problem in areca nut and betel quid chewer population of Indian.[7],[11]

Leukoplakia is clinically a white patch, but pathologically, the changes are of hyper or parakeratosis and acanthosis, with or without cellular atypia or dysplasia. There is about 0%–20% chance of progression to invasive cancer depending on type of leukoplakia.[12]

Erythroplakia

It is a red patch with or without granular appearance and has increased risk of malignant transformation (8%–20%). It needs more aggressive interventions compared to leukoplakia.[12]

Oral submucous fibrosis

It is a premalignant condition characterized by submucosal fibrosis in oral cavity due to excessive deposition of fibroblasts and collagen fibers induced by carcinogens such as arecoline, tobacco, etc. OSF presents in various stages from whitish discoloration to papules with erosive ulcers. The carcinogens inhibit the phagocytosis of fibroblasts and collagen which leads to their abnormal deposition.[12]

Lichen planus

It is an autoimmune oral mucosal inflammatory condition affecting mainly the buccal mucosa with a 6%–10% risk of changing into SCC. The variants of lichen planus such as reticular, popular, atrophic, ulcerative, bullous, and plaque forms have been described in literature.[7],[12]

Squamous cell carcinoma

SCC of gingivobuccal area has different morphologic subtypes and associated biological behavior [Figure 2].

A verrucous carcinoma is an exophytic growth with warty appearance and submucosal invasion with broad pushing well-defined tumor cells. Biologically, this is usually a locally destructive cancer without metastatic potentials especially in its pure form. Many a time, excision of the entire lesion finds out areas of dedifferentiation and invasive garden variety of SCC.[13]

A papillary SCC is uncommon variant characterized by papillary proliferations and is also noninvasive and nonmetastatic in its pure form.[14]

Conventional invasive SCC has typically keratinized or non-keratinized cells with nuclear pleomorphism with or without vascular, lymphatic, and perineural invasion. This is the most common variety of SCC detected in gingivobuccal area.[15]

Sarcomatoid SCC is a rare variant having sarcoma-like spindle cell features. These are typically invasive with aggressive course showing resistance to conventional radiotherapy and chemotherapy.[16]

Basaloid SCC has poor cellular differentiation, necrosis, hyaline material and keratin pearl formation. Clinically, this is very aggressive carcinoma compared to other forms.[17]

Diagnosis

History

Complete history with an assessment of risk factors is extremely important as etiologies such as tobacco and areca nut chewing can predispose the patient for field cancerization and possibilities of detecting multicentric disease.

The primary GBC tumor is usually ulcerative and infiltrative rather than exophytic. Careful assessment of SMF is important as in the absence of SMF; trismus suggests deeply infiltrative disease. The symptom of temporal headache and facial pain on the affected side needs a radiological evaluation for perineural spread to the skull base. Extension of the primary lesion to other subsites mobility of the lesion over mandible and skin involvement are important findings for management. Clinical evidence of paramandibular spread or retromolar trigone involvement is best evaluated by palpation, especially by bimanual method between fingers in oral mucosa and on skin.

Regional lymph node examination is an integral part and pattern of lymph node metastasis from OCC is defined. Level I, II, and III Lymph nodes are the most common metastatic site for GBC and spread to nodes in posterior triangle in the absence of metastasis at these levels is rare. An adequate examination of the neck should assess the presence or absence of palpable lymphadenopathy; the number, location and size of nodes; and any clinical manifestations of extracapsular extension of disease, such as fixation of overlying skin, soft tissue, or paralysis of cranial nerves.[18],[19],[20]

Distant metastasis is quite rare ranging from 8% to 17%, and the most common site is the lung, liver and bone in that order.[21]

Investigations

Apart from investigations to define comorbidities and chronic medical conditions, most of the imaging and laboratory tests are defined to stage the disease and consequently help selection of treatment as well as prognostication. Investigations are also useful for posttreatment evaluations.

Primary tumor

Tissue diagnosis

Biopsy under topical or local anesthesia is easy outpatient clinic procedure in most of the cases and gives adequate information in most of the cases. In case of verrucous lesions, deep biopsies are needed, and sometimes, excision of entire lesion only gives true diagnosis. Patients with SMF may need evaluation and biopsy under general anesthesia.[22],[23]

Imaging

Soft-tissue extent of disease is critical in upper GBC for infratemporal fossa (ITF) involvement and to assess perineural skull base extension. Lower GBC needs to be evaluated for para mandibular spread and perineural spread in extensive lesions. Multidetector contrast-enhanced computed tomography (CT) scan from skull base to clavicle in all three planes is a common choice of investigation and contrast-enhanced MRI can better detect marrow involvement as well as perineural involvement. Gross involvement of mandible can be seen on orthopantomogram; however, minimal cortical involvement is best imaged on bone window CT scan.[24] Hybrid methods (positron emission tomography [PET]/CT, PET/magnetic resonance imaging, and single photon emission computed tomography/CT) have their role in some special situations for locally advanced primary, recurrent or salvage situations.[25]

Neck

Imaging

A simple, repeatable, cost-effective, noninvasive tool such as ultrasonography (USG) can provide extremely important information. USG findings are more correlated with the pathologic findings than palpation; however, CT gives the most effective and reliable results when it is combined with USG in neck staging. Preoperative USG and CT scanning of the neck by an experienced radiologist are essential and useful for diagnosis, staging, and therapy choices.[26]

Tissue diagnosis

USG-guided FNAC can be a useful tool in doubtful or post-treatment situations.[25]

Distant metastases

Investigations

Conventionally, a chest radiograph and abdominal USG were done to exclude gross possible metastasis for head-and-neck squamous cancer. Plain high-resolution CT of thorax is a better and effective alternative to X-ray. Whole body PET-CT provides better information for not only distant metastasis or second primaries but also the possibility of involvement of regional nodes. Functional imaging (PET-CT) improves the initial staging and the detection of residual or recurrent disease following therapy.[25],[27]

Accurate staging provides the basis of appropriate selection of therapy and subsequent reporting of end results. Tumor node metastasis staging proposed by the American Joint Comity on Cancer and the International Union against Cancer is the widely used staging system all worldwide.[28]

Decision-Making in Gingivobuccal Cancer Treatment

Aims

The paramount objective of curing the patient is well understood. However, preservation of form and function, and when not possible restoration of same; obtaining good quality of life has become the equally important aim of treatment. Reducing the sequelae of the treatment and prevention of second primary cancer also needs consideration. The risk of death from a second primary cancer in patients with early-stage cancer of the head and neck is higher than the risk of dying of the original primary.[29]

Surgery and radiotherapy are the mainstay curative treatments. Chemotherapy is being used as palliative or in neoadjuvant setups in special situations. Depending on the site of GBC (Alveolus, GB sulcus, or pure buccal mucosa), the extent of primary tumor and status of lymph nodes, the treatment of these cancers may be surgery or radiation therapy used alone or in combination, with or without chemotherapy. Stage, proximity to mandible and its location anteriorly or posteriorly influences the initial treatment choices of GBC.[30],[31],[32],[33]

Age and general medical conditions are important for tolerating optimal treatment plan. Patient's occupation, tolerance, acceptance, and compliance do influence the choice of initial treatment. Socioeconomic considerations as well as availability of therapeutic facilities also play a major role. A successful management team not only includes head-and-neck surgical oncologist, radiation oncologist, and medical oncologist but also plastic and reconstructive surgeon, dentist, rehabilitation expert, physiotherapist, nutritionist, and oncopsychologist, etc.

Early lesions (T1–T2) can be effectively treated with either surgery or radiation as single modality. Surgery is choice of treatment when SMF is associated. Surgery is also preferred for the lesions located in lower GB sulcus (may or may not be involving mandible) as radiation causes osteoradionecrosis (ORN) in these situations.[31] Advanced lesions require multimodality treatment with surgery as initial part of management when the disease is operable.[34]

Surgical aspects of gingivobuccal cancer treatment

Management of primary

Removal of entire primary cancer with clear tumor-free margins three-dimensionally is the goal of surgical resection. In case of field cancerization or SMF, margins are usually widely taken almost encompassing the entire buccal mucosa complex. Surgical approaches for GBC are per oral, lower cheek flap-lip split, visor flap and rarely upper cheek flap, depending on size and location of the primary. Different surgical tools such as CO2 laser for early cancers, ultrasonic scissors for ITF clearance and precision saw for mandibular cuts are used to facilitate tumor clearance as well as functional and esthetic preservation. Per oral resection is only advisable in small lesions situated anteriorly with adequate mouth opening and without gross mandibular involvement.[35] Posterior-based tumors require special attention in clearance of soft tissue toward ITF. Different schools have suggested different management of ITF disease in the form of upfront compartmental clearance, use of neoadjuvant chemotherapy, etc., with varied results.[32],[33],[34]

Management of mandible

The concept of “commando operation” warranting the need for an in-continuity “composite resection” of uninvolved mandible is obsolete as no lymphatic channels pass through the mandible. Sacrificing the normal uninvolved mandible to gain access to the primary tumor or to accomplish an in-continuity composite resection is no longer justified.[36] Segmental or hemimandibulectomy is indicated only when (1) mandible is grossly involved by cancer, (2) invasion of soft tissue of inferior alveolar canal by tumor, and (3) Massive soft-tissue disease adjacent to mandible – para mandibular spread.

Mandibular periosteum is a significant protective barrier and usually in dentate patients, the tumor advances from buccal or buccogingival sulcus area toward the alveolus and through the dental socket into the cancellous part of bone invading mandible in that fashion rather than direct invasion of periosteum and mandibular cortex [Figure 5], [Figure 6], [Figure 7].[37],[38]

This forms the bases of justification of marginal mandibulectomy in patients even with early invasion of mandible, since the mandibular cortex inferior to the roots of the teeth remains free and can be safely preserved.[37],[39] This kind of marginal mandibulectomy can be done over horizontal ramus (conventional rim resection) or both horizontal and vertical ramus (L shaped). In edentulous, tumor approaches to alveolar process and then infiltrates the dental pores extending to cancellous part of the mandible. The vertical height of the body of mandible recedes in edentulous patients and minimum 1 cm height of residual mandible required for successful, marginal mandibulectomy is not achievable most of the times. In postradiated mandible, marginal mandibulectomy is contraindicated as (1) the ability of periosteum as barrier to the tumor is lost (2) the chances of ORN are high in residual mandible.[37],[39],[40]

There is literature evidence that point of mandibular entry of tumor is at abutment, which in both the dentate and edentulous jaw is often at the junction of the reflected and attached mucosa.[39] However, this might be more so for the floor mouth and alveolar cancers compared to BA sulcus cancers. Of all GBC, the cancers of retromolar trigone are extremely aggressive and mandible and pterygoid region invasion occur early.[41] Inferior dental and lingual nerve involvement are also frequent. L-shaped marginal mandibulectomy can be only done in carefully selected early cases. Most of these patients require segmental or hemimandibulectomy with ITF clearance.

Management of neck

The most important prognostic factor for head-and-neck SCC is presence of cervical lymph node metastasis.[42] Size of metastatic lymph nodes, number of nodes, level of involvement, extranodal spread, and tumor emboli in the intervening lymphatics also influence prognosis.[43] The pattern of lymph node metastasis from GBC is well established.[20] The management of clinically N0 neck has been addresses by many. A recent single institute randomized controlled trial advocates elective neck dissection.[44] In a clinically well-investigated N0 neck with T1-2 primary, an educated, motivated patient can be offered close observation of neck with therapeutic intervention at a further date if required as the chances of occult neck node metastasis is <20% in this scenario.[45],[46],[47] Frozen section of lymph nodes at level II, III, and IV can be useful in T3 and T4 primaries [Figure 8] and [Figure 9].[48]

Supra omohyoid neck dissection removing I, II, and III lymph node levels is adequate in the absence of clinically positive neck and alleviates the morbidity caused by full neck dissection, improving quality of life. Anteriorly based buccal and BA cancers with negative neck can also be offered level IIB sparing supra omohyoid neck dissection reducing neck dissection morbidity further down.[49],[50]

On the other hand, for clinically positive neck, full neck dissection removing Level I to Level V is mandatory. However, in clinically doubtful cases, frozen section of supra omohyoid neck dissection specimen can help to decide further neck management. Preservation of accessory nerve, sternomastoid muscle and internal jugular vein depends on intraoperative findings, level of lymph node metastasis, and presence of extracapsular spread (modified neck dissection).

In spite of its significant functional and esthetic morbidity, radical neck dissection still remains the treatment of choice in patients presenting with N2b or N3 disease and/or recurrent disease. All efforts should be made to preserve the accessory nerve if it is not involved clinically in this situation. Control of regional disease in neck is not compromised by preservation of the accessory nerve and almost all these patients require adjuvant radiation because of their gross nodal status.[51] Bilateral neck dissection is required for clinically involved neck and in case of certain predictive factors such as tumor and location.[52]

Reconstructive procedures of the head-and-neck region should give acceptable result regarding both functional and esthetic outcome. The decision of modality should be tailor-made taking into consideration multiple factors. Reconstructive options range from leaving a raw post-CO2 laser excision area to complex microvascular reconstructions, depending on the extent of resection, health of patient, willingness of patient, previous treatment taken, socioeconomic considerations and expertise available.[55],[56],[57]

In carefully selected patients, pectoralis major myocutaneous flap (PMMCF) can also be placed esp. when microvascular techniques are not available or as salvage of free flap failure.[58]

PMMCF was considered a great advance in the history of head-and-neck reconstructive surgery, as it allows an abundant block of well-vascularized tissue to be harvested with technical ease close to the cervicofacial area and facilitates reconstruction in a single surgical operation, with a low level of morbimortality.[59],[60]

Although the PMMF was the method of choice for many years, advances in microsurgery techniques have constrained their gradual introduction, so the indications for the pectoralis flap have undergone a regression at the expense of an increase in the indications for free flaps.

In complex defects where segmental or larger mandibular defect is produced, reconstruction is challenging as it not only involves the esthetics but also important functional aspects.

Radiotherapy as primary modality is rarely used as surgery is expeditious, provides pathology for examination; allowing identification of prognostic factors. Side effects such as xerostomia, mucositis, dysphagia and more so for GBC-ORN are the reasons for general selection of surgery as first line of treatment. Early OCCs are highly curable and patients are at high risk of developing second cancers which might be less amenable to function preserving surgeries, and hence, radiation can be kept reserved for such eventualities. Therefore, primary radiotherapy is reserved only for patients with significant comorbidities or with special desires and for large inoperable primary or recurrent tumors.[61]

Adjuvant radiotherapy

Adjuvant radiation therapy is employed for improvement in locoregional disease control in postoperative settings.[62] Advance pathological Stage (III and IV), positive margins, perineural invasion, tumor spillage, multiple positive nodes, and extracapsular spread are standard indications for adjuvant radiotherapy. Relative factors to be looked at in the context of the overall clinical picture are depth of invasion more than 5 mm, close margins, irregular pattern of invasion with infiltrative margins, and poor differentiation.[63]

Standard adjuvant radiotherapy is external beam radiation of 60 Gray given once daily in fractions of 2 Gy, comprising of 30/33 fractions. Side effects such as xerostomia, mucositis, dysgeusia, and ORN also occur in adjuvant radiotherapy settings. ORN is most significant complication and the risk factors are health of dentition, volume of mandible within the field of radiation and dosage, as well as blood supply of residual mandible. Prevention with prophylactic dental care before starting radiation is mandatory.[64]

Reirradiation

Conventionally, it is believed that re-irradiation gives unacceptable long-term complications. With sophisticated radiotherapy machines and advances in delivery systems, such as IMRT, cyber knife, proton beam, now it is possible to re-irradiate these patients with reasonably acceptable toxicity profile.[65],[66],[67]

Chemotherapy

Chemotherapy as primary line of treatment or as single modality treatment has no role in GBC. Induction or neoadjuvant chemotherapy has provided good results in T4b cases; however, there is scarcity of adequate literature to draw conclusions is also experimental especially in borderline operable cases.[34],[68] Adjuvant chemotherapy alone has no role in GBC but has been proved to be useful for high-risk cases along with radiotherapy.[63],[69]

Intra-arterial chemotherapy

Recently, this approach is being studied more showing high response rates even in previously treated patients.[70] This modality is logistically demanding and real benefit over conventional intravenous chemotherapy still needs to be proven.

Chemoradiation

Chemotherapy is indicated in combination with adjuvant radiation therapy in selected high-risk GBC patients in adjuvant post-operative settings. Positive surgical margins and extranodal spread are presently acceptable high-risk situations where adjuvant chemoradiation therapy is justified. Other situations where it might be considered in context of overall picture are perineural invasion, advanced T and/or N stage especially positivity at Level IV or Level V and vascular embolism.[63],[62]

Rehabilitation

Rehabilitation should start from initial consultation taking care of functional aspects of oral cavity, dental and prosthetic issues, and psychosocial aspects. A very interactive coordination between the team players including surgeon, radiation and medical oncologist as well as medical staff, psycho-oncologist, dietician, speech therapist, dentist, prosthodontist, social workers, along with the patient, family are caretakers is essential for a complete satisfactory rehabilitative outcome.[71]

Results

The outcomes in GBC have been evaluated at major head-and-neck centers across the country with a generally poor prognosis for lesions in Stage III, Stage IV and specially with ITF extension. Walvekar et al.[6] in a retrospective review of 2275 patients diagnosed with tumors of the gingivobuccal complex over 3 years noticed 35.5% recurrence rate at a median follow-up of 2.51 years with a median postrecurrence survival of 2.7 months. The 2- and 5-year DFS rates were 63.8% and 53.3%, respectively. Tumor depth and metastatic lymphadenopathy were found to be independent prognostic factors for disease-free survival. Dewan et al.[72] reported an 11-year Institutional experience of 203 cases with superior gingivobuccal sulcus tumors receiving surgical intervention with ITF involvement in 55 of them. The 10-year overall survival and disease-free survival was observed to be 39 and 52%, respectively, with a median follow-up of 15 months. The overall survival was 40 and 36%, respectively, in cases with and without ITF clearance. Similarly, the disease-free survival was found to be 58 and 49%, respectively, in cases with and without ITF clearance. After analyzing the various studies on the GBC, we found early stage GBCs to have about 70%–85% survival rate compared to 20%–40% in advanced stage.[1],[18],[31],[32],[33],[34],[72],[73] Site-specific control rate for buccal mucosa, alveolar ridge, and retromolar trigone show an overall survival rate of 52%–63%, 50%–65%, and 20%–55.3%, respectively.[1],[33],[73],[74]

Quality of life

There is recent increase in awareness to use these outcome parameters and is still in its developing stage. There are some twenty different head-and-neck-related QOL measures, with differences to surgical or nonsurgical treatment. Although limited patient population, studies have shown following determinant factors.[72],[75],[76]

Selective neck dissection has minimum morbidity compared to full neck

Transoral resections have better outcome

Pedicle flaps do worse than free flaps.

Follow-up

The goal of regular clinical follow-up examination is to prevent recurrence, minimize morbidity, and detect second primary or metastatic disease. In the initial phase, importance is given to rehabilitation, improvement in QOL and early detection of recurrences in high-risk cases. Later on, more importance is given to oncological screening and secondary and tertiary prevention.[71],[77]

At all instance elimination of risk factors such as tobacco, beetle nut, alcohols, and chronic trauma are given due importance. Chemoprevention of oral carcinogenesis is at present of research interest and there are no recommendations for routine use of chemoprevention due to lack of data on safety and usefulness.[78],[79]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.